Resistance to a group of natural products including the anthracyclines has been shown, in experimental animal tumor models, to be based on an energy-dependent outward drug transport system. This process serves to limit drug accumulation so that lethal levels are not reached. Our preliminary studies have shown that outward transport process can be antagonized by the acridinylmethanesulfonanilide m-AMSA, several relatively non-toxic acridines and certain other natural products. The proposed study is designed to examine use of such agents as a means of circumventing modes resistance to anthracyclines and other drugs involving enhanced exodus. Studies using combinations of anthracyclines + acridines and other agents will be designed to quantitate promotion of anthracycline responsiveness in drug-resistant cell lines. Appropriate kinetic studies will be carried out to assess the characteristics of the exodus process, and the persistence of exodus inhibition by second agents. The relationship between persistence of exodus inhibition vs. concentration and time of exposure to exodus-modifying agents will be examined. Based on results of these experiments and determinations of plasma half-life of different acridines, combination schedules will be devised and tested in animals bearing transplantable tumors varying in anthracycline resistance. Enhanced drug exodus, as a mode of resistance to response to anthracyclines in human granulocytic leukemias and human solid tumors, will be assessed. The ultimate goal of this project is the identification of modes of promotion of anthracycline responses in drug-resistant tumors in man. During later years of this project, adriamycin-acridine combinations, and other combinations suggested by earlier studies, can be tested against human solid tumor cells in a clonogenic assay system.